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The Doc-Phd toxin-antitoxin system inhibits bacterial translation via an unknown mechanism. Functional and structural analyses now show that Doc, which has an active site like AMPylating Fic proteins, actually works as a kinase, phosphorylating EF-Tu to block translation.
Identification of antibacterials and then their mechanism of action using metabolic suppression profiling uncovers inhibitors targeting glycine metabolism, PABA and biotin biosynthesis.
Assembled helical maquettes have been used to mimic basic oxidoreductase activities, but the requisite design symmetry limited advanced functions. Construction of a single-chain protein now enables intra- and interprotein electron transfer and complex cofactor interactions at rates comparable to those of natural proteins.
Spiran rings appear in numerous natural products, but the mechanism of their formation is not always clear. Reconstitution of the spirotryprostatin pathway now reveals that distinct biochemical mechanisms, one catalyzed by an enzyme from an unrelated pathway, lead to related spiran-containing structures.
The bacterial glmS riboswitch is unique in that the bound glucosamine-6-phosphate ligand acts as a cofactor for ribozyme-mediated RNA cleavage. In vitro selection and crystallographic analysis reveal that three mutations convert glmS from a cofactor-dependent to a metal ion–dependent ribozyme.
A set of tetravalent antigens reveals that low-affinity interactions between an allergen epitope and IgE antibodies contribute to allergic responses through FcɛRI receptors on mast cells, and inhibiting these low-affinity epitopes prevents degranulation.
Nematodes define a new role for sirtuins in lifespan extension, in which the sirtuin product nicotinamide is converted to a substrate for aldehyde oxidase; turnover of this enzyme generates hydrogen peroxide, causing upregulation of defense mechanisms that promote longevity.
Phenotypic screening using a reporter for Notch trafficking and processing leads to the identification of five compounds that affect this pathway, including one that acts at a pre-ER exit step in a manner distinct from known molecules.
The anesthetic propofol binds in a cavity on the β subunit of the GABAA receptor between the transmembrane and extracellular domains, near other residues that have been shown to be important for determining anesthetic sensitivity.
Polyketide synthases infrequently insert β-branched monomers into their growing polyketide chains, the details of which are not well established. Bioinformatic, structural and mutational analyses now define a core motif and surface residues in acyl carrier proteins that govern insertion of β-branched units.
Isolation and characterization of the first hydroxyproline O-arabinosyltransferases demonstrates overlapping and distinct functions in glycosylating protein substrates and controlling plant development.
A 'lockdown' mechanism explains why the CLC-ec1 Cl−/H+ antiporter is selective against F− ions, whereas Cl− and other inorganic ions are moved indiscriminately.
Crystal structures of α-L-iduronidase, the enzyme linked to MPS I, now provide snapshots of the catalytic pathway and rationalize the role of 100 disease-related mutations, while biochemical analysis of deglycosylated and mutated enzymes define roles for non–active site residues in controlling function.
IC50 values are widely used measures of compound potency. A multiparametric analysis of dose-response curves derived from a panel of cell lines treated with anticancer drugs reveals that there can be systematic variability in dose-response parameters across drug classes and cell types, effects that are not apparent by inspection of IC50 values.
Inteins catalyze protein splicing, excising themselves from the final polypeptide sequence. Biochemical and structural analysis of multiple inteins now demonstrates that these constructs can swap domains before splicing, leading to unexpected hybrid products.
EZH2 and EED are components of the Polycomb repressive complex 2 (PRC2), a ‘writer’ complex involved in histone methylation. A stapled peptide that disrupts the EZH2-EED interaction arrests growth in PRC2-dependent leukemia cells and offers an alternative mode for EZH2 inhibition.
Opsinamides are nonretinoid inhibitors that compete with 9-cis-retinal for binding to melanopsin Opn4 without affecting rod- and cone-mediated visual responses but affecting tolerance to light and light exacerbation of migraine.
The metallothionein-like, 23-amino-acid peptide NO-inducible nitrosothionein does not protect against heavy metal toxicity like its homologues, but instead helps relieve nitrosative stress by reaction of six cysteine residues to form SNO adducts, which are recycled back to thiols by thioredoxin.